Findings explain the mechanism by which the tumor suppressor puts the brakes on oncogenic Ras
By Jeffrey M. Perkel | January 18, 2007
The p53 tumor suppressor protein serves as the integration point for two separate signal transduction pathways, suggesting a mechanism by which p53 keeps cancer in check, according to a report published in this week's Science. The findings also clarify at the molecular level the well known, but poorly understood, crosstalk between receptor tyrosine kinase and TGF-beta signals.
"I thought it was a really beautiful story," Liliana Attisano of the University of Toronto, who was not involved in the study, told The Scientist. "It provides a really nice mechanistic insight into something we knew happened but we didn't know why."
The behavior of cells is regulated not by one single message, but by the combined efforts of several signals, explained Stefano Piccolo of the University of Padua, Italy, who led the study. Researchers are well versed in the meanings of individual "words" in this molecular vocabulary, he said; "The next layer that we need to address is how the different signals make up a meaningful message."
Piccolo's team was interested in the multiple messages conveyed by TGF-beta, which Piccolo calls "like Dr. Jekyll and Mr. Hyde." Though the protein promotes malignancy in cancerous cells, its normal function is to suppress cellular proliferation, like a molecular brake. Using Xenopus embryos and human cancer cell lines, Piccolo found that p53 is the molecular player at the heart of this dichotomy. "When p53 is there, TGF-beta is a tumor suppressor," Piccolo said. "And when the cancer mutates p53, this sets the stage for the transition to metastasis."
Receptor tyrosine kinases provide the first piece of the puzzle. RTK signaling (for instance, via the FGF receptor) activates the Ras/MAPK cascade, which results in phosphorylation of p53 on two N-terminal serine residues by casein kinase I. Piccolo's team showed that this phosphorylated form of p53 is then competent to physically complex with the downstream effectors of TGF-beta signaling -- Smad transcription factors - and thus alter gene expression programs. "We found a way to activate p53 that is completely novel," Piccolo said.
In Xenopus embryos, this phosphorylation event is restricted to a belt around the embryo called the marginal zone. As only those cells with N-terminally phosphorylated p53 are able to respond to the TGF-beta signal, FGF signaling thus defines which cells can respond to TGF-beta and differentiate into mesoderm.
In human cells, the result is cytostasis, a proliferative block that serves to keep early-stage cancers in check, at least temporarily. Many developing cancers acquire mutations in Ras that render the protein constitutively active relatively early in their oncogenic transformation, and yet remain benign. This study suggests that p53 acts to suppress the proliferative tendency of activated Ras through TGF-beta signaling. "That's why cancer cells get selected for losing [p53]," Piccolo speculated. "The fire is kept under control by the water -- the TGF-beta -- and so there is a lot of pressure to get rid of this brake."
Though he doesn't dispute the central claim of the paper -- that p53 is the integrator for these two signaling pathways -- Joseph Schlessinger, chairman of the department of pharmacology at the Yale University School of Medicine, said he takes issue with some of the experimental approaches the authors used. "For example," he said, "they used kinase inhibitors and dominant negative blockers -- these are not ideal tools to prevent action of protein kinases, because they can block the action of several protein kinases."
For her part, Attisano questioned the widespread generality of data derived from just two human cell lines. "It would be nice to know how generally applicable this observation is," she said. "Can they look now in samples from cancer patients and see these alterations in phosphorylation?"
Jeffrey M. Perkel
Links within this article:
ML Phillips, "Cell death unnecessary for tumor suppression," The Scientist, September 6, 2006.
M. Cordenonsi et al., "Integration of TGF-beta and Ras/MAPK signaling through p53 phosphorylation," Science, published online 18 January 2007. DOI:10.1026/science.1135961.
J.M. Perkel, "Researchers are getting specific about protein kinase inhibitors," The Scientist, 16:37, Sept. 2, 2002.